Overview

Tumoral calcinosis (also referred to as hyperphosphataemic tumoral calcinosis) is a condition that involves high phosphate levels in the blood, producing abnormal calcium deposits in soft tissues around the large joints, forming lumps. The condition affects both men and women and is more common in people of African and Middle Eastern descent. The condition is either primary (inherited) or secondary, arising as a complication of other medical conditions. The exact cause of developing tumoral calcinosis remains inconclusive, but it can be due to abnormal calcium and phosphate metabolism. Early diagnosis can prevent complications like limited mobility, joint damage, or infection.^{1, 2, 3}

What body parts does tumoral calcinosis affect?

Lumps from tumoral calcinosis are usually painless and found near the joints. These lumps consist of hydroxyapatite crystals and calcium carbonate. Tumoral calcinosis most commonly affects:

• Hips
• Wrists
• Elbows
• Shoulders
• Jaw
• Spinal cord 
• Feet^{1, 2}

What are the causes of tumoral calcinosis?

Tumoral calcinosis occurs either as a result of genetic mutations (primary) or as a secondary cause of other medical conditions.

Primary (genetic mutation) tumoral calcinosis

Primary tumoral calcinosis is an inherited metabolic disorder. One in every three individuals with this condition inherits the mutated gene for fibroblast growth factor (FGF) from either of their parents. This gene helps bone cells to produce FGF23 protein. In some cases, GALNT3 and KL genes are mutated, which regulate the FGF23 production and are therefore affected. FGF23 protein usually regulates the phosphate reabsorption into the kidneys from the blood. During dysregulation, kidneys absorb excess amounts of phosphate. Rather than flushing out excess phosphate in the urine, it binds with calcium and forms lumps in soft tissues. A person who inherits the mutated gene may develop the disease or act as a carrier, passing it to the next generation without having the disease.^{1, 2} 

When both parents are carriers, each child has a:

• 1 in 4 chance of not inheriting the mutated gene (no risk of the disease).
• 1 in 4 of developing tumoral calcinosis.
• 1 in 2 chance of being a carrier without developing tumoral calcinosis.^{1, 2}

Secondary tumoral calcinosis

Secondary tumoral calcinosis develops as a complication of other medical conditions that imbalance the calcium-phosphate levels. The medical conditions include:

• Chronic kidney disease
• Hyperparathyroidism
• Vitamin D metabolism disorders³

Approximately 1.6% of patients on peritoneal dialysis develop secondary tumoral calcinosis.⁴

What are the symptoms of tumoral calcinosis?

Tumoral calcinosis symptoms differ based on the calcium deposit’s size and location. Typical symptoms include:

• Hard, painless lumps near the joints (some may feel soft to touch).
• Difficulty moving joints.
• Muscle pain, bone pain, or joint pain in a few cases.
• Localised tenderness.
• Increased local temperature.
• Redness.
• Fever.
• Anaemia.
• Eye discomfort and itching.
• Dental defects.
• Skin ulceration^{1, 2.}

Laboratory investigations in tumoral calcinosis

Although symptoms often suggest tumoral calcinosis, laboratory tests confirm the diagnosis by identifying biochemical abnormalities and underlying causes.

Serum biochemical markers

Calcium and phosphate levels

• Increased serum phosphate levels (one of the prominent features of tumoral calcinosis).
• Serum calcium levels usually remain normal^{1, 2} 

Parathyroid hormone levels (PTH)

• Changes in PTH levels help to differentiate between primary and secondary causes of tumoral calcinosis. 
• Low PTH levels suggest primary tumoral calcinosis, and high PTH levels suggest secondary causes like hyperparathyroidism.^{1, 2} 

Vitamin D levels

• Increased 1,25-dihydroxyvitamin D levels can promote phosphate retention and contribute to calcium deposition.^{1, 2} 

Alkaline phosphatase levels

• Serum alkaline phosphatase levels remain normal in most cases.⁵ Mild elevations are seen in a few cases.⁶

Genetic testing

• Identifying genetic mutations in FGF23, GALNT3, or KL genes confirms the primary tumoral calcinosis and differentiates it from secondary causes
• Genetic tests are usually suggested when clinical and laboratory tests are inconclusive for suspected cases to identify the specific gene associated with the condition¹
• According to the literature, fewer than 100 cases have been confirmed through genetic testing

Renal function tests

• Increased blood urea nitrogen (BUN) and serum creatinine levels in chronic renal failure contribute to tumoral calcinosis^2,5 

Inflammatory markers

• Increased C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels in chronic kidney disease, autoimmune diseases, or infections suggest secondary tumoral calcinosis
• Inflammatory markers help to distinguish inflammatory-mediated calcium deposition from genetic forms⁷

Other relevant investigations

• Other relevant investigations include estimating urine calcium and phosphate levels. The ratio of tubular maximum reabsorption of phosphate (TmP) to glomerular filtration rate (GFR) (TmP/GFR) increases in tumoral calcinosis.⁸

Imaging studies

Laboratory investigations show biochemical evidence of tumoral calcinosis. Imaging studies (X-rays or plain radiographs, CT (computerised tomography), or magnetic resonance Imaging (MRI) of the calcium deposits confirm the diagnosis of tumoral calcinosis.

• X-ray: Shows mixed and characteristic calcified masses
• CT scan: Provides a detailed picture of calcified masses
• MRI scan: Shows associated bone and joint changes or surrounding tissue involvement

Doctors evaluate both the laboratory test results and imaging tests to confirm the diagnosis of tumoral calcinosis. Early investigation can help prevent complications and improve treatment outcomes.^1,9

Differential diagnosis

Other conditions that can cause calcium deposition in soft tissues include:

• Normophosphataemic tumoral calcinosis, a genetic disorder, occurs due to calcium deposition in skin and mucosae with constant pain and serious skin infections
• Porphyria cutanea tarda, a metabolic disorder, occurs because of a uroporphyrinogen III decarboxylase enzyme deficiency
• Calcinosis cutis, a cutaneous condition, occurs due to calcium salt deposition in the skin and subcutaneous tissue
• Pseudohypoparathyroidism, a rare genetic disorder, occurs due to resistance to parathyroid hormone
• Chronic renal failure
• Fibrodysplasia ossificans progressive, a rare genetic condition, occurs when bone replaces muscles and connective tissues, resulting in painful new bone growth
• Osteomyelitis, an inflammatory condition, occurs because of microbial infection, causing bone destruction^{1, 2}

Challenges and limitations of laboratory investigations

Laboratory test findings may sometimes overlap with other medical conditions, such as chronic kidney disease, and complicate the diagnosis of tumoral calcinosis. Additionally, genetic testing may not always be accessible or affordable in resource-limited settings. Therefore, imaging tests are often necessary to confirm the diagnosis.^{1, 2} 

Summary

Tumoral calcinosis is a rare condition where calcium deposits in soft tissues surrounding the large joints. This condition can be either primary (inherited) or secondary (developing as a complication of other medical conditions, such as chronic kidney disease or hyperparathyroidism). A series of blood tests helps check calcium, phosphate, parathyroid hormone, vitamin D, and alkaline phosphatase levels, and genetic testing helps to detect the condition. These tests also help to differentiate primary tumoral calcinosis from secondary causes. Laboratory tests provide valuable information about biochemical imbalances and the underlying genetic predisposition in tumoral calcinosis. Early diagnosis through laboratory tests is essential to prevent further complications, such as joint damage, and improve patient outcomes. Along with laboratory tests, imaging (X-rays, CT scans, or MRIs) can also be performed to visualise the calcium deposits.